Title : Structure-conserved, sequence-divergent RNA motifs in Nipah virus reveal mutation resistant therapeutic targets missed by protein centric design
Abstract:
Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus emerging in South and Southeast Asia. With mortality rates ranging from 40–70%, it is classified by the World Health Organization as a priority pathogen. Despite its major clinical impact, the regulatory potential of the NiV genome remains incompletely understood. Currently, the majority of antiviral targeting focuses on viral proteins, but RNA secondary structures within viral genomes can serve important regulatory roles that make it a promising target. Functional RNA structures may remain conserved even as the nucleotide sequence diverges, making them difficult to detect using sequence-based analyses alone.
In this study, we applied a comparative computational framework to systematically identify structurally conserved RNA elements across the NiV genome. A total of 88 NiV genome sequences were aligned using Multiple Alignment Fast Fourier Transform (MAFFT), followed by analysis with a 120-nucleotide sliding window. Sequence variability was quantified using Shannon entropy, while structural conservation was assessed using the Structure Conservation Index (SCI) derived from RNAfold and RNAalifold. Candidate regions were defined as genomic windows exhibiting both moderate-to-high sequence variability and high structural conservation, indicative of evolutionarily constrained RNA motifs.
Our analysis identified four candidate regions where SCI remained in the top 5% (SCI: 0.98 – 1.0) of the data and sequence divergence in the top 50% (Shannon entropy: 0.65 – 0.76). These regions likely represent conserved RNA structural elements that may play important regulatory roles in the viral life cycle.
These findings highlight evolutionarily conserved RNA structures within the NiV genome as promising targets for further functional validation. Such elements may be particularly amenable to RNA-targeted therapeutic strategies, including antisense oligonucleotides and small-molecule RNA-binding compounds, offering a potential pathway toward the development of mutation-resistant antiviral interventions.
